Since old days, it has been believed that nerve cells are not regenerated. However, since culturing of nerve stem cells in undifferentiated conditions have succeeded in about 1990, it has become clear that there are stem cells capable of differentiating into nerve cells even in adult brain and that nerve can be regenerated.
Nerve stem cells are cells which have a self-replicating ability and also have multipotency capable of producing nerve cells (neurons) and supporting cells such as astrocytes and oligodendrocytes. Usually, nerve cells are formed from undifferentiated nerve stem cells via nerve precursor cells. It has been also known that embryonic stem cells (ES cells), bone marrow cells (myeloid stem cells, etc.) and the like are capable of differentiating into nerve cells. At present, in the art which is ahead of the times such as in the art for regeneration of bone and skin tissues, it is possible to achieve an object to some extent by reappearance of the physical conditions inherent to the tissues. However, in order to use nerve regeneration as a medical art, it is not sufficient that nerve cells are just physically formed but how to mature and how to function the nerve cell is an important problem.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease are diseases which occur when nerve cell death takes place in a progressive manner. With regard to a method for treating such neurodegenerative diseases, a supplementary treatment in which deficiency of neurotransmitter is supplemented or a symptomatic treatment has been mostly carried out at present. However, in the supplementary treatment or the symptomatic treatment, progress of degeneration of the nerve cannot be completely suppressed but symptom proceeds. It has been known however that, even in such diseases, endogenous nerve stem cells existing in adult brain are differentiated into nerve cells. For example, it has been reported that, in ischemic model animals, nerve regeneration takes place from nerve stem cells (J. Neurosci., 18, 7768-7778 (1998)).
In recent years, as an object of treatment of those neurodegenerative diseases, attempts for activating the inherent nerve stem cells and regenerating the disordered nerve tissue and function have been conducted (Nature Medicine, 4, 1313-1317 (1998); Nature Medicine, 6, 271-277 (2000)). Attempts where nerve stem cells are prepared from embryonic stem cells and aborted human brain or also from tissues of a patient per se and nerve regeneration is aimed by means of transplant have been conducted as well (Nature, 405, 951-955 (2000); Eur. J. Neurosci., 10, 2026-2036 (1998)). In addition, an effect for improving the symptoms by administration of stem cells from peripheral blood vessel has been shown not only in neurodegenerative diseases but also in demyelinated diseases (Nature, 422, 688-694 (2003)).
In the meanwhile, it has been reported that 2-propylpentanoic acid derivatives have an action for improving the function of astrocytes and accordingly that they are useful as treating agent and/or preventive agent for neurodegenerative diseases, neural dysfunction after cerebrospinal wound and cerebral stroke, brain tumor, cerebrospinal diseases accompanied by infectious diseases, and the like (e.g., EP-A-0632008).
Such 2-propylpentanoic acid derivatives have been also reported to be useful as a treating agent and/or a preventive agent for Parkinson's disease or Parkinson's syndrome (e.g., EP-A-1174131).
Furthermore, actions as such of the 2-propylpentanoic acid derivatives have been reported to be due to an action for improving the function of abnormally activated astrocytes causes by action of decreasing of intracellular S100β content (e.g., Tateishi, N. and eight others, Journal of Cerebral Blood Flow & Metabolism, 22, 723-734 (2002)).
It has been also reported that, in mature rat where axon of sciatic nerve is cut, the axon is elongated and kinetic function is recovered when 2-propylpentanoic acid is administered (e.g., Xia Zhang and six others, Brian Research, 975, 229-236 (2003)).
In those literatures, however, there is no description that 2-propylpentanoic acid derivatives accelerate growth and differentiation of nerve stem cells and nerve precursor cells and there is no reference that they have an action of inducing nerve cells from non-nervous cells such as glia cells. Furthermore, there has been neither description nor suggestion at all for a method where 2-propylpentanoic acid derivatives are used for cell preparation of nerve cells for transplant.
In spite of the fact that neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease are serious diseases resulting in deficiency of nerve, an effective method for the treatment of the diseases which is not a symptomatic one has not been found yet. For example, if only cutting of axon takes place in neurodegenerative disease as shown in animal models mentioned in the above document (Xia Zhang and six others, Brian Research, 975, 229-236 (2003)), there is a possibility that administration of 2-propylpentanoic acid can be used as an effective treating method. However, neurodegenerative disease is a general name for diseases in which not only axon but nerve cell itself gradually dies and no specific method for treating it has been found yet. In addition, no art has been found yet for inducing transplanted stem cells or endogenous stem cells to actually functioning nerve cells in stem cell transplant or in activation of endogenous stem cells which may be used as an effective treating method for neurodegenerative diseases in near future.
In view of the problems in the treatment of neurodegenerative diseases as such, there has been a brisk demand in the actual medical fields at present for the development of compounds which are useful as medicaments such as preventive agents and treating agents for neurodegenerative diseases.